PROJECT SUMMARY/ABSTRACT Thyroid cancer is the most common endocrine malignancy and incidences are rising. Thyroid cancers of follicular cell origin stand out among solid tumors because many of the tumor-initiating genetic events are known. Activating mutations of effectors of the MAPK signaling pathway are associated with both follicular and papillary thyroid cancer, and occur throughout the spectrum of thyroid diseases from benign adenomas through therapeutically refractive poorly-differentiated disease. Despite sharing activation of the MAPK pathway, activation via different effectors in the pathway results in distinct and unique pathological outcomes, including metastasis to distinct distant sites. We do not understand how activation of a single pathway via different mutations within the signaling cascade results in different pathological outcomes and recruitment of different tumor microenvironments. This paradigm is seen not only in thyroid cancer, but in other malignancies. We will utilize recently generated mouse models of thyroid cancer to model follicular and papillary thyroid cancers to study how activation of the oncogene Hras versus Braf affects tumor development and can modify the tumor microenvironment. We hypothesize that mode of activation contributes to stromal recruitment and extracellular matrix (ECM) modification, thus contributing to the pathobiology of tumor formation and progression. The data generated in these studies will provide a better understanding of the mechanisms by which different oncogenic events that activate the same pathway predisposes the development distinct pathological outcomes. We hope to use these data to develop novel therapeutic and prevention strategies for thyroid cancer.